Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), B cell lymphoproliferative primary effusion lymphoma (PEL) and multicentric Castleman's disease. KSHV latent viral genome, latent viral gene expression, deregulated secretion of cytokines, and aggressive angiogenic factors are critical for KS, PEL and MCD. Current treatments for KS and PEL rely on less effective cytotoxic systemic chemotherapeutics developed for non-virus-associated cancers that target DNA replication of all dividing cells. These treatment approaches have multiple myelosuppressive side effects, especially in immunocompromised patients. Hence, there is a critical need to design safe anti-viral therapies that simultaneously target tumors and eradicate viral load. Our long-term goal is to evaluate the role of arachidonic acid pathways of the host in KSHV biology. Our exciting studies discovered that 1) KSHV infection, aside from hijacking proinflammatory cyclyoxygenase-2 and 5-lipoxygenase pathways, significantly reduces the secretion of anti-inflammatory lipoxin LXA4; 2) KSHV infected cells and human KS lesion cells express lipoxin receptor ALXR, and more importantly 3) Incubation of KSHV infected cells with stable small molecule analogs of LXA4s and aspirin triggered lipoxins significantly downregulate KSHV's latent gene expression and decreases the infected cell survival. From these novel observations, we hypothesize that anti-inflammatory lipoxins mediate adverse effects on KSHV latency while at the same time, KSHV strategically reduces lipoxin secretion to maintain its latency and the survival of latently infected cells. To test this hypothesis, we have formulated three specific aim in which we will decipher the links between lipoxins, KSHV life cycle, and pathogenesis. Since current prevention and treatment options for KS and PEL are inadequate, the studies to evaluate the role of less explored lipoxins, aspirin triggered lipoxins, and their targetable receptor ALXR in KSHV's latency and pathogenesis are expected to reveal new and innovative therapeutic approaches. Our studies are significant and will have a positive impact by advancing the unexplored field of anti-inflammatory lipoxins in KSHV biology, and understanding their antiviral and anticancer potential can also be applied to other viral malignancies.